Cultured cells derived from transformed human and rat liver will be used (i) as a rapid assay for detecting the potential of chemicals to interact with DNA; (ii) to determine if both the human and rat metabolize the chemical; (iii) to predict if the rat is an appropriate species for a long term cancer bioassay; (iv) to validate that the in vitro rat system reflects the in vivo response; and (v) to isolate mutant/variant cell sublines incapable of metabolizing promutagens/procarcinogens. Preliminary studies indicate HepG2, a human cell line derived from the liver, and R1, a cell line derived from a rat hepatoma, metabolize promutagens/procarcinogens to a DNA damaging form, easily detected at low levels by ovservation of the induction of sister-chromatid-exchange (SCE). We propose to extend these easily performed assays to a variety of chemicals which represent major classes of procarcinogens. We will compare the response of the rat hepatoma cell to the response of bone marrow cells and hepatocytes in vivo. We propose to isolate mutants/variants of these cell lines which cannot metabolize promutagens/procarcinogens to a cytotoxic state. These selected clones will be analyzed for phenotypic complementation. These studies will permit somatic genetic techniques to be brought to bear on the problem of metabolism of promutagens/procarcinogens. Such studies may provide insight into the molecular mechanisms of metabolism, especially any differences between the rat and man.